Breaking tolerance leads to autoantibody production but not autoimmune liver disease in hepatitis B virus envelope transgenic mice.
Breaking tolerance leads to autoantibody production but not autoimmune liver disease in hepatitis B virus envelope transgenic mice.
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DOI：
10.4049/jimmunol.154.5.2504
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发表时间：
1995-03
影响因子：
4.4
通讯作者：
Susanne Wirth;L. Guidotti;K. Ando;H. Schlicht;F. Chisari
中科院分区：
文献类型：
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作者：
Susanne Wirth;L. Guidotti;K. Ando;H. Schlicht;F. Chisari
在小鼠白蛋白启动子的转录调控下，含有乙肝病毒包膜开放阅读框的乙肝病毒转基因小鼠在所有肝细胞中表达乙肝表面抗原，并将其分泌到循环中。由于这些转基因小鼠没有表现出自发性肝细胞损伤或对病毒(自身)抗原的自身免疫的迹象，我们询问是否可以通过诱导急性坏死性肝炎或用乙肝病毒包膜蛋白免疫来逆转自身耐受状态，目的是建立慢性免疫介导性肝炎的转基因模型。我们的研究表明，重复注射细菌内毒素、干扰素-γ或乙肝表面抗原特异性CTL，均可导致肝细胞损伤和炎症，但不会破坏T或B细胞水平的耐受性，提示这些药物诱导的肝内淋巴单核细胞浸润由非特异性细胞组成。即使在非转基因环境中提供适当的T细胞帮助时，转基因B细胞对乙肝表面抗原免疫完全有反应，过继转移非转基因小鼠的非转基因CD4+T细胞并不能诱导转基因B细胞产生抗HBs自身抗体。在CFA中用纯化的HBs Ag免疫转基因小鼠，并重复感染rHBVVV，可产生T细胞依赖性的抗HBs自身抗体，清除血清中的HBs Ag，但不能激活HBs Ag特异的CTL。结论：在该模型中，乙肝病毒包膜转基因小鼠对转基因产物在T细胞水平上有很大的耐受性，但在B细胞水平上不能耐受，抗-HBs应答的激活不足以诱发自身免疫性肝病。
Hepatitis B virus (HBV) transgenic mice containing the HBV envelope open reading frame under the transcriptional control of the mouse albumin promoter express hepatitis B surface Ag (HBsAg) in all of their hepatocytes and secrete HBsAg (10 to 40 ng/ml) into the circulation. Because these transgenic mice show no signs of spontaneous liver cell injury or autoimmunity toward the viral (self-) Ag, we asked whether the state of self-tolerance could be reversed by the induction of an acute necroinflammatory liver disease or by immunization with HBV envelope proteins, with the aim of creating a transgenic model for chronic, immune-mediated hepatitis. Our studies indicate that repetitive administration of bacterial LPS, IFN-gamma, or HBsAg-specific CTL, all of which were previously shown to cause liver cell injury and inflammation, does not break tolerance at the T or B cell level, suggesting that the intrahepatic lymphomononuclear cell infiltrate induced by these agents consists of HBsAg-nonspecific cells. The adoptive transfer of HBsAg-primed nontransgenic CD4+ T cells into transgenic mice did not induce anti-HBs autoantibody production by transgenic B cells, even though transgenic B cells were fully responsive to immunization with HBsAg when appropriate T cell help was provided in a nontransgenic environment. Immunization of transgenic mice with purified HBsAg in CFA and repetitive infection with rHBV envelope vaccinia virus led to production of T cell-dependent anti-HBs autoantibodies that cleared HBsAg from the serum, but not to activation of HBsAg-specific CTL. We conclude that HBV envelope transgenic mice are largely tolerant to the transgene product at the T cell but not at the B cell level, and that the activation of an anti-HBs response was not sufficient to induce an autoimmune liver disease in this HBV envelope transgenic mouse model.